The natural pigmentation of the skin stems from a mechanism that has now been clearly described: the melanocytes present in the stratum basale epidermidis produce melanin pigments which are synthesized in the melanosomes. Melanin synthesis (melanogenesis) increases under the action of UV radiation. The physiological function of tanning which ensues thus aims to protect the skin against UV radiation.
Various dysfunctions in the melanin production mechanism (due to an excess of external aggressions, hormonal disturbances or aging) induce the emergence of brown spots, particularly in the form of ephelides (freckles), and solar or senile lentigines.
Modifying the natural pigmentation of the skin is a desire shared by European, Asian and American women, although the underlying rationales differ: a white complexion is considered beautiful by some, while others seek to attenuate senile lentigo, considered to reveal aging. In Asia, as is the case in Europe and America, controlling skin pigmentation is thus a sensitive subject and the object of considerable demand.
Three key enzymes are involved in melanogenesis: tyrosinase and tyrosine-related proteins (TRP-1 and TRP-2). All three are glycoproteins located in the melanosome membrane. Out of the three, tyrosinase is the limiting enzyme in that it catalyzes the first two stages in pigment formation: ortho-hydroxylation of tyrosine to yield L-DOPA, then oxidation of the latter to yield dopaquinone. TRP-1 and TRP-2 are reported to intervene, in part, by stabilizing tyrosine hydroxylase.
In addition, it is known that stimulation of melanogenesis involves increasing intracellular cAMP levels. cAMP regulates the action of a protein kinase, PKC-b, whose ability to phosphorylate tyrosinase is determinant in melanin synthesis. In support of this mechanism, it has been observed that UV radiation very significantly increases PKC-b in cultured melanocytes.
Lastly, the role played by intracellular calcium in melanocyte metabolism is also undoubtedly to be taken into account.
To influence skin pigmentation, it is therefore possible to envisage degrading melanin, offering melanogenesis inhibitors which interact with the various targets described above, or even inhibiting the distribution of melanin in the epidermal cell layers.
However, the most frequently selected target is undoubtedly tyrosine hydroxylase, since it constitutes a limiting step in the process.
For a considerable time, depigmentation or lightening the skin was achieved using very potent products such as hydroquinone, sulfur- or non-sulfur-containing phenolic compounds and ascorbic acid. However, those products were not devoid of irreversible hypopigmentation effects and induced irritation. All those products are to be used in an efficacy/safety context that is not appropriate for cosmetics.
In the cosmetic field, the problem was tackled by using various retinoid derivatives, AHA, kojic acid and arbutin. The good results obtained in vitro on cellular cultures are seldom reproduced for use in vivo.
Hydroquinone, arbutin and kojic acid were developed for their competitive inhibition of tyrosinase or inhibition of the catalytic activity indispensable to tyrosinase function by chelation of copper ions. However, those products are difficult to use and may induce adverse effects.
There is thus a strong demand for innovative cosmetic products that are effective in vivo and non-toxic.
Increasing the intracellular rate of cAMP is also the objective of the slimming active ingredients. Indeed intracellular cAMP is essential to activate the glycerol release via adipocyte lipase (HSL): by this way, there is a depletion of cell lipid materials, and hence a decrease in cell volume.
Following the generation of slimming active substances based on direct activation of the lipolysis via phosphodiesterase inhibition (e.g., caffeine), more sophisticated products emerged. Those products address either to the stimulation of membrane receptors and their systems of intracellular transduction (protein G), or to their inhibition (receptors alpha and neuropeptide Y). All these approaches aim at increasing the rate of intracellular cAMP.
However, an original and alternative route may exist even opposite with the system supporting the increase of intracellular pool of cAMP with an aim of lipolysis stimulation.
The central role played by the intracellular calcium in the metabolism of the pre-adipocyte and the mature adipocyte is a well documented phenomenon and it is clear that the Ca++ takes part in several different ways in the installation of the fatty mass. Whereas this one, by an entering flow, inhibits the initial differentiation of pre-adipocytes by decreasing the triglycerides storage, it plays an opposite role in the final phase of differentiation like in the mature adipocyte by supporting the lipogenesis. To understand this phenomenon it should be known that there is a structural and functional connection between the membrane sites of the calcium entry and the adenylate cyclase.
By blocking calcium entry, the initial phase of differentiation is supported because the calcium-dependent post-mitosis inhibition is then raised, and the final phase of differentiation is disadvantaged by blocking the lipogenesis.
It is well-known in Pharmacology that an entering calcium flow supported by norepinephrine (α-adrenergic agonist) can be blocked by α1 antagonists such as prazosine and to a lesser extent by β1-adrenergic antagonists. In addition, it is known that within a adipocyte population more than 60% of the cells express the α1 et β1-adrenergic receptors.
This brake by adrenergic antagonists is translated in pre-adipocyte and the adipocyte by a differentiation markers reduction which are glycerol-3-phosphate dehydrogenase (G-3-PDH) and “peroxisome proliferator-activated receptor gamma” (PPARγ), as well as by a triglycerides storage reduction.
To fight effectively against the pads and capitons, the consumers push cosmetic industry with the development of increasingly powerful active ingredients.